Bendamustine is a nitrogen mustard used in the treatment of chronic lymphocytic leukemias and lymphomas and is also being studied for the treatment of sarcoma. It belongs to the family of drugs referred to as alkylating agents.
The synthesis of bendamustine hydrochloride monohydrate has been reported by Ozegowski and Krebs, J. Praktische Chemie, 4(20), 178-186 (1963) and by Gao et al., Chinese Journal of New Drugs, 16(23), 1960-1, 1970 (2007). However, these publications do not specify the purity of the bendamustine hydrochloride monohydrate obtained by the described processes, or the method used for drying of the initially obtained wet product (i.e., bendamustine hydrochloride containing water in addition to the water of crystallization present in the bendamustine hydrochloride monohydrate) to the desired monohydrate form. Bendamustine hydrochloride containing water in various amounts in addition to the water of crystallization present in the monohydrate form of bendamustine hydrochloride is referred to herein as “water-wet” (or simply “wet”) or “partially dried.”
Published PCT application WO 2010/144675 describes in Example 23, step B, a recrystallization procedure for bendamustine which included the drying of water-wet bendamustine hydrochloride monohydrate after an acetone rinse using a flow of humidified nitrogen (35% to 60% relative humidity). However, this publication does not report the yield of the recrystallized product or the amount of water present in the initial filter cake before drying with the humidified nitrogen. Due to the relatively high solubility of bendamustine hydrochloride monohydrate in mixtures of acetone and water, rinsing of a water-wet filter cake of bendamustine hydrochloride monohydrate with such mixtures can result in a significant yield loss of the product. This loss of product during an acetone wash is clearly detrimental should such a washing step be included as part of a commercial process for producing bendamustine hydrochloride monohydrate. Additionally, bendamustine has been found to be susceptible to hydrolytic degradation upon prolonged exposure to excessive moisture, resulting in the generation of the undesired contaminant monohydroxy-bendamustine (the chemical structures of bendamustine hydrochloride monohydrate and monohydroxy-bendamustine are shown in FIG. 1). However, overdrying of bendamustine hydrochloride monohydrate, resulting in the loss of the desired water of crystallization, can occur if the drying conditions used are too vigorous.
Consequently, there is a need for improved methods for drying water-wet bendamustine hydrochloride monohydrate, whereby high yields of the desired product, which is substantially free of water in excess of the single water of crystallization, are obtained while avoiding overdrying and the formation of degradation by-products.